The origin of and causes for schizophrenia, one of the most serious neuropsychiatric disorders, have long been sought after. A number of studies have suggested that schizophrenia is predominantly genetic, but it has proven difficult to show a significant genetic linkage. However, recently, a novel locus associated with inherited susceptibility to schizophrenia has been mapped to chromosome 1 q21-q22, near the anonymous DNA markers D1S1653, D1S1679, and D1S1677 (Brzustowicz et al., 2000). Furthermore, several lines of evidence, both from morphological and neuropsychological findings, now indicate that schizophrenia may be a disease of central nervous system development (reviewed in Stefan et al, 1997). For example, Falkai et al., 2000, provided quantitative data showing that the positioning of neuron (pre-alpha cell) clusters was abnormal in schizophrenia patients, supporting the theory that schizophrenia derives from impaired brain development. Such abnormal neuron positions could, e.g., arise from failures of neuronal migration during fetal development.
An important pathway implicated in the development of the nervous system, as well as in schizophrenia, is the Notch signaling pathway. Notch is a protein receptor for inhibitory signals that shape the pattern of the nervous system, and the localization of Notch signaling is crucial for determining where neural precursor cells arise (Baker, 2000). In a series of 80 British parent-offspring trios, the NOTCH4 locus was highly associated with schizophrenia (Wei and Hemmings, 2000). Possible candidate sites conferring susceptibility to schizophrenia included an A-to-G substitution in the promoter region, and the (CTG)n repeat in exon 1, of NOTCH4.
The presenilin proteins, i.e., presenilin 1 (PS1, encoded by the PS1 gene) and 2 (PS2, encoded by the PS2 gene), are involved in the Notch pathway, and form a close functional relationship with Notch during cell fate determination in a variety of species (Selkoe, 2000). Several lines of evidence have suggested roles for PS1 and PS2 genes in developmental, apoptotic signaling and in the regulation of proteolytic cleavage of the β-amyloid precursor protein (βAPP) (Levitan et al., 1995; Wong et al., 1997; Shen et al., 1997; Wolozin et al., 1996; De Strooper et al., 1998). For example, the PS1 gene is associated with migration defects in the central nervous system of PS1−/−mice (Hartmann et al., 1999; Handler et al., 2000). In addition, a mutation in βAPP (βAPPA1a713Val) has been described in one family with a schizophrenia-like illness (Jones et al., 1992), further implicating the PS1/βAPP/Notch pathways in schizophrenia and related disorders. However, just how these putative functions are mediated, and how they relate to the abnormal metabolism of the βAPP associated with PS1 and PS2 mutations remains to be elucidated (Martin et al., 1995; Scheuner et al., 1996; Citron et al., 1997; Duff et al., 1996; Borchelt et al., 1996). The identification and cloning of normal as well as mutant PS1 and PS2 genes and gene products are described in detail in co-pending commonly assigned U.S. application Ser. No. 08/431,048, filed Apr. 28, 1995; Ser. No. 08/496,841, filed Jun. 28, 1995; Ser. No. 08/509,359, filed Jul. 31, 1995; and Ser. No. 08/592,541, filed Jan. 26, 1996, the disclosures of which are incorporated herein by reference.
A new protein which specifically interacts with PS1 and PS2 has recently been discovered. This transmembrane protein, herein referred to as “Presenilin Associated Membrane Protein” or “PAMP”, is expressed in multiple tissues (e.g., brain, kidney, lung, etc.). PAMP is described in co-pending commonly assigned U.S. application Ser. No. 09/541,094, filed Mar. 31, 2000, which is specifically incorporated herein by reference. The PAMP gene and gene product is implicated in the biochemical pathways affected in Alzheimer's Disease (AD), and may also have a role in other dementias, amyloid angiopathies, and developmental disorders such as spina bifida. Interestingly, the gene associated with inherited susceptibility to schizophrenia (see Brzustowicz, supra) also contains the PAMP gene (Yu et al, 2000).
A need exists for new methods and reagents to more accurately and effectively diagnose and treat schizophrenia as well as other neuropsychiatric, neurodevelopmental, and neurodegenerative diseases. In addition, further insights into PAMP and its interaction with PS proteins and other components may lead to new diagnostic and treatment methods for schizophrenia and other related CNS diseases.